International Journal of Molecular Sciences

Editorial

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Open AccessEditorial

The Role of Autotaxin and LPA Signaling in Embryonic Development, Pathophysiology and Cancer

by Christiana Magkrioti, Eleanna Kaffe and Vassilis Aidinis

Int. J. Mol. Sci. 2023, 24(9), 8325; https://doi.org/10.3390/ijms24098325 - 05 May 2023

Cited by 3 | Viewed by 1260

Abstract

Autotaxin (ATX) or Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) is a secreted enzyme with lysophospholipase D activity, with its primary function being the extracellular hydrolysis of lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), a bioactive lipid [...] Full article

(This article belongs to the Special Issue The Role of Autotaxin and LPA Signalling in Embryonic Development, Pathophysiology and Cancer)

Research

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10 pages, 1831 KiB

Open AccessArticle

Autotaxin Has a Negative Role in Systemic Inflammation

by Ioanna Nikitopoulou, Aggeliki Katsifa, Paraskevi Kanellopoulou, Edison Jahaj, Alice G. Vassiliou, Zafeiria Mastora, Ioanna Dimopoulou, Stylianos E. Orfanos, Vassilis Aidinis and Anastasia Kotanidou

Int. J. Mol. Sci. 2022, 23(14), 7920; https://doi.org/10.3390/ijms23147920 - 18 Jul 2022

Cited by 5 | Viewed by 1580

Abstract

The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types [...] Read more.

The pathogenesis of sepsis involves complex interactions and a systemic inflammatory response leading eventually to multiorgan failure. Autotaxin (ATX, ENPP2) is a secreted glycoprotein largely responsible for the extracellular production of lysophosphatidic acid (LPA), which exerts multiple effects in almost all cell types through its at least six G-protein-coupled LPA receptors (LPARs). Here, we investigated a possible role of the ATX/LPA axis in sepsis in an animal model of endotoxemia as well as in septic patients. Mice with 50% reduced serum ATX levels showed improved survival upon lipopolysaccharide (LPS) stimulation compared to their littermate controls. Similarly, mice bearing the inducible inactivation of ATX and presenting with >70% decreased ATX levels were even more protected against LPS-induced endotoxemia; however, no significant effects were observed upon the chronic and systemic transgenic overexpression of ATX. Moreover, the genetic deletion of LPA receptors 1 and 2 did not significantly affect the severity of the modelled disease, suggesting that alternative receptors may mediate LPA effects upon sepsis. In translation, ATX levels were found to be elevated in the sera of critically ill patients with sepsis in comparison with their baseline levels upon ICU admission. Therefore, the results indicate a role for ATX in LPS-induced sepsis and suggest possible therapeutic benefits of pharmacologically targeting ATX in severe, systemic inflammatory disorders. Full article

(This article belongs to the Special Issue The Role of Autotaxin and LPA Signalling in Embryonic Development, Pathophysiology and Cancer)

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29 pages, 3423 KiB

Open AccessArticle

Lysophosphatidic Acid Is a Proinflammatory Stimulus of Renal Tubular Epithelial Cells

by Christiana Magkrioti, Georgia Antonopoulou, Dionysios Fanidis, Vaia Pliaka, Theodore Sakellaropoulos, Leonidas G. Alexopoulos, Christoph Ullmer and Vassilis Aidinis

Int. J. Mol. Sci. 2022, 23(13), 7452; https://doi.org/10.3390/ijms23137452 - 05 Jul 2022

Cited by 3 | Viewed by 2418

Abstract

Chronic kidney disease (CKD) refers to a spectrum of diseases defined by renal fibrosis, permanent alterations in kidney structure, and low glomerular-filtration rate. Prolonged epithelial-tubular damage involves a series of changes that eventually lead to CKD, highlighting the importance of tubular epithelial cells [...] Read more.

Chronic kidney disease (CKD) refers to a spectrum of diseases defined by renal fibrosis, permanent alterations in kidney structure, and low glomerular-filtration rate. Prolonged epithelial-tubular damage involves a series of changes that eventually lead to CKD, highlighting the importance of tubular epithelial cells in this process. Lysophosphatidic acid (LPA) is a bioactive lipid that signals mainly through its six cognate LPA receptors and is implicated in several chronic inflammatory pathological conditions. In this report, we have stimulated human proximal tubular epithelial cells (HKC-8) with LPA and 175 other possibly pathological stimuli, and simultaneously detected the levels of 27 intracellular phosphoproteins and 32 extracellular secreted molecules with multiplex ELISA. This quantification revealed a large amount of information concerning the signaling and the physiology of HKC-8 cells that can be extrapolated to other proximal tubular epithelial cells. LPA responses clustered with pro-inflammatory stimuli such as TNF and IL-1, promoting the phosphorylation of important inflammatory signaling hubs, including CREB1, ERK1, JUN, IκΒα, and MEK1, as well as the secretion of inflammatory factors of clinical relevance, including CCL2, CCL3, CXCL10, ICAM1, IL-6, and IL-8, most of them shown for the first time in proximal tubular epithelial cells. The identified LPA-induced signal-transduction pathways, which were pharmacologically validated, and the secretion of the inflammatory factors offer novel insights into the possible role of LPA in CKD pathogenesis. Full article

(This article belongs to the Special Issue The Role of Autotaxin and LPA Signalling in Embryonic Development, Pathophysiology and Cancer)

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18 pages, 2337 KiB

Open AccessArticle

ENPP2 Promoter Methylation Correlates with Decreased Gene Expression in Breast Cancer: Implementation as a Liquid Biopsy Biomarker

by Maria Panagopoulou, Andrianna Drosouni, Dionysiοs Fanidis, Makrina Karaglani, Ioanna Balgkouranidou, Nikolaos Xenidis, Vassilis Aidinis and Ekaterini Chatzaki

Int. J. Mol. Sci. 2022, 23(7), 3717; https://doi.org/10.3390/ijms23073717 - 28 Mar 2022

Cited by 11 | Viewed by 2447

Abstract

Autotaxin (ATX), encoded by the ctonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) gene, is a key enzyme in lysophosphatidic acid (LPA) synthesis. We have recently described ENPP2 methylation profiles in health and multiple malignancies and demonstrated correlation to its aberrant expression. Here we focus [...] Read more.

Autotaxin (ATX), encoded by the ctonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) gene, is a key enzyme in lysophosphatidic acid (LPA) synthesis. We have recently described ENPP2 methylation profiles in health and multiple malignancies and demonstrated correlation to its aberrant expression. Here we focus on breast cancer (BrCa), analyzing in silico publicly available BrCa methylome datasets, to identify differentially methylated CpGs (DMCs) and correlate them with expression. Numerous DMCs were identified between BrCa and healthy breast tissues in the gene body and promoter-associated regions (PA). PA DMCs were upregulated in BrCa tissues in relation to normal, in metastatic BrCa in relation to primary, and in stage I BrCa in relation to normal, and this was correlated to decreased mRNA expression. The first exon DMC was also investigated in circulating cell free DNA (ccfDNA) isolated by BrCa patients; methylation was increased in BrCa in relation to ccfDNA from healthy individuals, confirming in silico results. It also differed between patient groups and was correlated to the presence of multiple metastatic sites. Our data indicate that promoter methylation of ENPP2 arrests its transcription in BrCa and introduce first exon methylation as a putative biomarker for diagnosis and monitoring which can be assessed in liquid biopsy. Full article

(This article belongs to the Special Issue The Role of Autotaxin and LPA Signalling in Embryonic Development, Pathophysiology and Cancer)

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16 pages, 1595 KiB

Open AccessArticle

Phospholipase A1 Member A Activates Fibroblast-like Synoviocytes through the Autotaxin-Lysophosphatidic Acid Receptor Axis

by Yang Zhao, Stephan Hasse, Myriam Vaillancourt, Chenqi Zhao, Lynn Davis, Eric Boilard, Paul Fortin, John Di Battista, Patrice E. Poubelle and Sylvain G. Bourgoin

Int. J. Mol. Sci. 2021, 22(23), 12685; https://doi.org/10.3390/ijms222312685 - 24 Nov 2021

Cited by 5 | Viewed by 2419

Abstract

Lysophosphatidylserine (lysoPS) is known to regulate immune cell functions. Phospholipase A1 member A (PLA1A) can generate this bioactive lipid through hydrolysis of sn-1 fatty acids on phosphatidylserine (PS). PLA1A has been associated with cancer metastasis, asthma, as well as acute coronary syndrome. However, [...] Read more.

Lysophosphatidylserine (lysoPS) is known to regulate immune cell functions. Phospholipase A1 member A (PLA1A) can generate this bioactive lipid through hydrolysis of sn-1 fatty acids on phosphatidylserine (PS). PLA1A has been associated with cancer metastasis, asthma, as well as acute coronary syndrome. However, the functions of PLA1A in the development of systemic autoimmune rheumatic diseases remain elusive. To investigate the possible implication of PLA1A during rheumatic diseases, we monitored PLA1A in synovial fluids from patients with rheumatoid arthritis and plasma of early-diagnosed arthritis (EA) patients and clinically stable systemic lupus erythematosus (SLE) patients. We used human primary fibroblast-like synoviocytes (FLSs) to evaluate the PLA1A-induced biological responses. Our results highlighted that the plasma concentrations of PLA1A in EA and SLE patients were elevated compared to healthy donors. High concentrations of PLA1A were also detected in synovial fluids from rheumatoid arthritis patients compared to those from osteoarthritis (OA) and gout patients. The origin of PLA1A in FLSs and the arthritic joints remained unknown, as healthy human primary FLSs does not express the PLA1A transcript. Besides, the addition of recombinant PLA1A stimulated cultured human primary FLSs to secrete IL-8. Preincubation with heparin, autotaxin (ATX) inhibitor HA130 or lysophosphatidic acid (LPA) receptor antagonist Ki16425 reduced PLA1A-induced-secretion of IL-8. Our data suggested that FLS-associated PLA1A cleaves membrane-exposed PS into lysoPS, which is subsequently converted to LPA by ATX. Since primary FLSs do not express any lysoPS receptors, the data suggested PLA1A-mediated pro-inflammatory responses through the ATX-LPA receptor signaling axis. Full article

(This article belongs to the Special Issue The Role of Autotaxin and LPA Signalling in Embryonic Development, Pathophysiology and Cancer)

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21 pages, 2481 KiB

Open AccessArticle

ENPP2 Methylation in Health and Cancer

by Maria Panagopoulou, Dionysios Fanidis, Vassilis Aidinis and Ekaterini Chatzaki

Int. J. Mol. Sci. 2021, 22(21), 11958; https://doi.org/10.3390/ijms222111958 - 04 Nov 2021

Cited by 10 | Viewed by 2273

Abstract

Autotaxin (ATX) encoded by Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) is a key enzyme in Lysophosphatidic Acid (LPA) synthesis implicated in cancer. Although its aberrant expression has been reported, ENPP2 methylation profiles in health and malignancy are not described. We examined in silico [...] Read more.

Autotaxin (ATX) encoded by Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) is a key enzyme in Lysophosphatidic Acid (LPA) synthesis implicated in cancer. Although its aberrant expression has been reported, ENPP2 methylation profiles in health and malignancy are not described. We examined in silico the methylation of ENPP2 analyzing publicly available methylome datasets, to identify Differentially Methylated CpGs (DMCs) which were then correlated with expression at gene and isoform levels. Significance indication was set to be FDR corrected p-value < 0.05. Healthy tissues presented methylation in all gene body CGs and lower levels in Promoter Associated (PA) regions, whereas in the majority of the tumors examined (HCC, melanoma, CRC, LC and PC) the methylation pattern was reversed. DMCs identified in the promoter were located in sites recognized by multiple transcription factors, suggesting involvement in gene expression. Alterations in methylation were correlated to an aggressive phenotype in cancer cell lines. In prostate and lung adenocarcinomas, increased methylation of PA CGs was correlated to decreased ENPP2 mRNA expression and to poor prognosis parameters. Collectively, our results corroborate that methylation is an active level of ATX expression regulation in cancer. Our study provides an extended description of the methylation status of ENPP2 in health and cancer and points out specific DMCs of value as prognostic biomarkers. Full article

(This article belongs to the Special Issue The Role of Autotaxin and LPA Signalling in Embryonic Development, Pathophysiology and Cancer)

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19 pages, 1687 KiB

Open AccessArticle

Increased Autotaxin Levels in Severe COVID-19, Correlating with IL-6 Levels, Endothelial Dysfunction Biomarkers, and Impaired Functions of Dendritic Cells

by Ioanna Nikitopoulou, Dionysios Fanidis, Konstantinos Ntatsoulis, Panagiotis Moulos, George Mpekoulis, Maria Evangelidou, Alice G. Vassiliou, Vasiliki Dimakopoulou, Edison Jahaj, Stamatios Tsipilis, Stylianos E. Orfanos, Ioanna Dimopoulou, Emmanouil Angelakis, Karolina Akinosoglou, Niki Vassilaki, Argyrios Tzouvelekis, Anastasia Kotanidou and Vassilis Aidinis

Int. J. Mol. Sci. 2021, 22(18), 10006; https://doi.org/10.3390/ijms221810006 - 16 Sep 2021

Cited by 20 | Viewed by 3319

Abstract

Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signaling in pulmonary injury, inflammation, and fibrosis. Here, [...] Read more.

Autotaxin (ATX; ENPP2) is a secreted lysophospholipase D catalyzing the extracellular production of lysophosphatidic acid (LPA), a pleiotropic signaling phospholipid. Genetic and pharmacologic studies have previously established a pathologic role for ATX and LPA signaling in pulmonary injury, inflammation, and fibrosis. Here, increased ENPP2 mRNA levels were detected in immune cells from nasopharyngeal swab samples of COVID-19 patients, and increased ATX serum levels were found in severe COVID-19 patients. ATX serum levels correlated with the corresponding increased serum levels of IL-6 and endothelial damage biomarkers, suggesting an interplay of the ATX/LPA axis with hyperinflammation and the associated vascular dysfunction in COVID-19. Accordingly, dexamethasone (Dex) treatment of mechanically ventilated patients reduced ATX levels, as shown in two independent cohorts, indicating that the therapeutic benefits of Dex include the suppression of ATX. Moreover, large scale analysis of multiple single cell RNA sequencing datasets revealed the expression landscape of ENPP2 in COVID-19 and further suggested a role for ATX in the homeostasis of dendritic cells, which exhibit both numerical and functional deficits in COVID-19. Therefore, ATX has likely a multifunctional role in COVID-19 pathogenesis, suggesting that its pharmacological targeting might represent an additional therapeutic option, both during and after hospitalization. Full article

(This article belongs to the Special Issue The Role of Autotaxin and LPA Signalling in Embryonic Development, Pathophysiology and Cancer)

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15 pages, 1762 KiB

Open AccessArticle

PDGFRα Enhanced Infection of Breast Cancer Cells with Human Cytomegalovirus but Infection of Fibroblasts Increased Prometastatic Inflammation Involving Lysophosphatidate Signaling

by Zelei Yang, Xiaoyun Tang, Todd P. W. McMullen, David N. Brindley and Denise G. Hemmings

Int. J. Mol. Sci. 2021, 22(18), 9817; https://doi.org/10.3390/ijms22189817 - 10 Sep 2021

Cited by 4 | Viewed by 2093

Abstract

Human cytomegalovirus (HCMV) infects 40–70% of adults in developed countries. HCMV proteins and DNA are detected in tumors and metastases, suggesting an association with increased invasion. We investigated HCMV infection in human breast cancer cell lines compared to fibroblasts, a component of tumors, [...] Read more.

Human cytomegalovirus (HCMV) infects 40–70% of adults in developed countries. HCMV proteins and DNA are detected in tumors and metastases, suggesting an association with increased invasion. We investigated HCMV infection in human breast cancer cell lines compared to fibroblasts, a component of tumors, and the role of platelet-derived growth factor receptor-α (PDGFRα). HCMV productively infected HEL299 fibroblasts and, to a lesser extent, Hs578T breast cancer cells. Infection of another triple-negative cell line, MDA-MB-231, and also MCF-7 cells, was extremely low. These disparate infection rates correlated with expression of PDGFRA, which facilitates HCMV uptake. Increasing PDGFRA expression in T-47D breast cancer and BCPAP thyroid cancer cells markedly increased HCMV infection. Conversely, HCMV infection decreased PDGFRA expression, potentially attenuating signaling through this receptor. HCMV infection of fibroblasts promoted the secretion of proinflammatory factors, whereas an overall decreased secretion of inflammatory factors was observed in infected Hs578T cells. We conclude that HCMV infection in tumors will preferentially target tumor-associated fibroblasts and breast cancer cells expressing PDGFRα. HCMV infection in the tumor microenvironment, rather than cancer cells, will increase the inflammatory milieu that could enhance metastasis involving lysophosphatidate. Full article

(This article belongs to the Special Issue The Role of Autotaxin and LPA Signalling in Embryonic Development, Pathophysiology and Cancer)

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Review

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Open AccessReview

Autotaxin-LPA-LPP3 Axis in Energy Metabolism and Metabolic Disease

by Anu Jose and Petra C. Kienesberger

Int. J. Mol. Sci. 2021, 22(17), 9575; https://doi.org/10.3390/ijms22179575 - 03 Sep 2021

Cited by 11 | Viewed by 5961

Abstract

Besides serving as a structural membrane component and intermediate of the glycerolipid metabolism, lysophosphatidic acid (LPA) has a prominent role as a signaling molecule through its binding to LPA receptors at the cell surface. Extracellular LPA is primarily produced from lysophosphatidylcholine (LPC) through [...] Read more.

Besides serving as a structural membrane component and intermediate of the glycerolipid metabolism, lysophosphatidic acid (LPA) has a prominent role as a signaling molecule through its binding to LPA receptors at the cell surface. Extracellular LPA is primarily produced from lysophosphatidylcholine (LPC) through the activity of secreted lysophospholipase D, autotaxin (ATX). The degradation of extracellular LPA to monoacylglycerol is mediated by lipid phosphate phosphatases (LPPs) at the cell membrane. This review summarizes and interprets current literature on the role of the ATX-LPA-LPP3 axis in the regulation of energy homeostasis, insulin function, and adiposity at baseline and under conditions of obesity. We also discuss how the ATX-LPA-LPP3 axis influences obesity-related metabolic complications, including insulin resistance, fatty liver disease, and cardiomyopathy. Full article

(This article belongs to the Special Issue The Role of Autotaxin and LPA Signalling in Embryonic Development, Pathophysiology and Cancer)

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